Development of Heteroaromatic Silicon Fluoride Acceptors (HetSiFAs) for <sup>18</sup>F-Labeled Radiopharmaceuticals
Silicon Fluoride Acceptors (SiFAs) enable <sup>18</sup>F-labeling of complex peptides via isotope exchange under exceptionally mild conditions. SiFA radiopharmaceuticals have been clinically validated for diagnosing and treating cancers as tracers for positron emission tomography (PET) and radiotwin theranostics. Despite these advances, conventional phenyl SiFAs (PhSiFAs) require complex substrate engineering to mask their lipophilicity, which complicates the design of new tracers. Here, we report a new and diverse class of heteroaromatic SiFA derivatives (HetSiFAs) that are significantly less lipophilic than classical PhSiFAs. We show that HetSiFAs retain suitable stability without compromising labeling kinetics. We highlight the performance of a pyrazole-HetSiFA for rapid and efficient <sup>18</sup>F-labeling within a model TATE-peptide and show that the resulting PET tracer clears through the kidneys with minimal defluorination in mice. Novel radiopharmaceuticals incorporating HetSiFAs can capitalize on the improved and flexible pharmacokinetic parameters and excellent <sup>18</sup>F-fluorination efficiency offered by these scaffolds.
Authors
- Prashant S. Deore (ORCID: https://orcid.org/0000-0003-3418-2378)
- C. Uribe Estrada (ORCID: https://orcid.org/0000-0002-2425-7340)
- HyunJune Jun
- Patrick DeRoy
- Afaf R. Genady (ORCID: https://orcid.org/0000-0002-7508-7847)
- Alexandre Larivée (ORCID: https://orcid.org/0009-0009-1470-5128)
- Christopher M. Waldmann
- Alexey Kostikov (ORCID: https://orcid.org/0000-0003-1646-761X)
- Ayman A. Ibrahim (ORCID: https://orcid.org/0000-0003-1862-405X)
- Saman Sadeghi (ORCID: https://orcid.org/0000-0002-2158-2703)
- Jean‐Philip Lumb (ORCID: https://orcid.org/0000-0002-9283-1199)
- Mohamed E. El‐Zaria
- Luis-Rafael Silva
- En Zhao
- Thomas A. Singleton (ORCID: https://orcid.org/0000-0003-1097-2148)
- Simon Edelmann (ORCID: https://orcid.org/0000-0002-7148-3279)
- Anton A. Toutov
- Yusra Mahmood Marfatia
- Darcy Burley
- Bren Jordan P. Atienza
- Julie Delecueillerie
Institutions
- Theranostics (New Zealand) (NZ)
- Paraza Pharma (Canada) (CA)
- Molecular Theranostics (United States) (US)
- McGill University (CA)
- McMaster University (CA)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01087
- Citations
- 2
- Primary Topic
- Radiopharmaceutical Chemistry and Applications
- Type
- article
- Field-Weighted Citation Impact
- 2.72
Funders
- Government of Ontario
- Canada Foundation for Innovation
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada